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Gabapentin (Neurontin) is a gamma-aminobutyric acid analogue indicated in adults for adjunctive treatment of partial seizures with or without secondary generalization. Two studies were conducted to determine the single-dose pharmacokinetics of gabapentin in healthy subjects age 1 month to 12 years and to guide dose selection in safety and efficacy trials in pediatric patients. Forty-eight subjects were given single oral doses of gabapentin (10 mg/kg) while fasting. Enrollment was homogeneously distributed throughout the age range. Plasma samples were drawn predose and then serially for 24 hours postdose. Single doses of gabapentin were well tolerated by healthy pediatric subjects. Plots of pharmacokinetic parameters versus age suggested significant differences between younger (1 month to < 5 years) and older (> or =5 to 12 years) subjects. Mean area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)) was 25.6 microg x h/mL in younger subjects and 36.0 microg x h/mL in older subjects (p < 0.001). Corresponding mean peak plasma concentrations (Cmax) were 3.74 and 4.52 microg/ml (p < 0.05). Oral clearance (normalized for body weight) was 7.40 and 4.41 mL/min/kg in younger subjects and older subjects, respectively (p < 0.001). It was concluded that children between 1 month and < 5 years of age require approximately 30% higher daily doses of gabapentin than those > or =5 to 12 years of age. [ABSTRACT FROM AUTHOR]

Background: Aprotinin, a hemostatic agent, regulates fibrinolysis, modulates the intrinsic coagulation pathway, stabilizes platelet function, and exhibits anti-inflammatory properties through inhibition of serine proteases, such as trypsin, plasmin, and kallikrein. Aprotinin has been used successfully for many years in cardiac operations, and there have been preliminary investigations of its use in hip replacement operations. The objectives of this multicenter, randomized, placebo-controlled, double-blind trial were to evaluate the efficacy and safety of aprotinin as a blood-sparing agent in patients undergoing an elective primary unilateral total hip replacement and to examine its effect on the prevalence of deep-vein thrombosis in this population.Methods: Seventy-three patients received a placebo; seventy-six patients, a low dose of aprotinin (a load of 500,000 kallikrein inhibitor units [KIU]); seventy-five, a medium dose of aprotinin (a load of 1,000,000 KIU, with infusion of 250,000 KIU per hour); and seventy-seven patients, a high dose of aprotinin (a load of 2,000,000 KIU, with infusion of 500,000 KIU per hour). The end points for the determination of efficacy were transfusion requirements and blood loss. Patients received standard prophylaxis against deep-vein thrombosis and underwent compression ultrasonography with color Doppler imaging of the proximal and distal venous systems of both legs to evaluate for the presence of deep-vein thrombosis.Results: Aprotinin reduced the percentages of patients who required any form of blood transfusion (47 percent of the patients managed with a placebo needed a transfusion compared with 28 percent of those managed with low-dose aprotinin [p = 0.02],27 percent of those managed with high-dose aprotinin [p = 0.008], and 40 percent of those managed with medium-dose aprotinin [p = 0.5]). Only 6 percent (twelve) of the 212 patients treated with aprotinin required allogeneic blood compared with 15 percent (ten) of the sixty-eight patients treated with the placebo (p = 0.03). Aprotinin decreased the estimated intraoperative blood loss (p = 0.02 for the low-dose group, p = 0.04 for the medium-dose group, and p = 0.1 for the high-dose group), the measured postoperative drainage volume (p = 0.4 for the low-dose group, p = 0.006 for the medium-dose group, and p = 0.000 for the high-dose group), and the mean reduction in the hemoglobin level on the second postoperative day (thirty-four grams per liter for the placebo group, twenty-eight grams per liter for the low-dose group [p = 0.000], twenty-six grams per liter for the medium-dose group [p = 0.000], and twenty-three grams per liter for the high-dose group [p = 0.0001). The rate of deep-vein thrombosis was similar for all groups.Conclusions: We concluded that aprotinin is safe and effective for use as a hemostatic agent in primary unilateral total hip replacements. In patients who are at high risk of receiving allogeneic blood, use of aprotinin may be of particular clinical and economic benefit. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of the α₇-nicotinic receptor agonist ABT-126 for treatment of cognitive impairment in stable subjects with schizophrenia who smoke., Methods: A 12-week double-blind, placebo-controlled, parallel-group study was conducted from August 2012 to March 2014. Subjects with a diagnosis of schizophrenia based on DSM-IV-TR criteria (confirmed by the Mini-International Neuropsychiatric Interview version 6.0.0) were randomized 1:1:1 to ABT-126 25 mg, ABT-126 75 mg, or placebo once daily while maintained on their background antipsychotic medication. The primary endpoint was the change from baseline on the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) neurocognitive composite score; the primary analysis compared ABT-126 with placebo at week 12 using a mixed-effects model for repeated measures. Secondary endpoints included the change from baseline on the University of California San Diego Performance-based Skills Assessment-2 Extended-Range, the 16-item Negative Symptom Assessment scale (NSA-16), and safety assessments., Results: Of the 157 randomized subjects, 82% completed the study. The mean baseline MCCB neurocognitive composite score for the entire study sample was 28.8; scores were similar across groups. No statistical difference in the change from baseline score between any of the ABT-126 dose groups and placebo was observed on the MCCB neurocognitive composite score (ABT-126 25 mg, +0.28; ABT-126 75 mg, +0.41; placebo, +1.42). Differences in the NSA-16 total score were seen with ABT-126 75 mg versus placebo at week 6 (-2.79; P = .011) and week 12 (-1.94; P = .053). Adverse events with ABT-126 were similar to placebo, except for constipation (5.8% for ABT-126 vs 0% for placebo)., Conclusions: ABT-126 did not demonstrate a procognitive effect in subjects with stable schizophrenia who smoke. A trend for improvement in negative symptoms was observed with the high dose. The safety profile of ABT-126 was similar to placebo., Trial Registration: ClinicalTrials.gov identifier: NCT01678755​., (© Copyright 2018 Physicians Postgraduate Press, Inc.)

Importance: Patients' previous experience with performance-based cognitive tests in clinical trials for cognitive impairment associated with schizophrenia can create practice-related improvements. Placebo-controlled trials for cognitive impairment associated with schizophrenia are at risk for these practice effects, which can be difficult to distinguish from placebo effects., Objectives: To conduct a systematic evaluation of the magnitude of practice effects on the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) in cognitive impairment associated with schizophrenia and to examine which demographic, clinical, and cognitive characteristics were associated with improvement in placebo conditions., Design, Setting, and Participants: A blinded review was conducted of data from 813 patients with schizophrenia who were treated with placebo in 12 randomized placebo-controlled clinical trials conducted mostly in outpatient clinics in North America, Europe, Asia, and Latin America from February 22, 2007, to March 1, 2014. A total of 779 patients provided data for the primary outcome measure at baseline and at least 1 follow-up. Seven trials had prebaseline assessments wherein the patients knew that they were not receiving treatment, allowing a comparison of practice and placebo effects in the same patients., Interventions: Placebo compared with various experimental drug treatments., Main Outcomes and Measures: Composite score on the MCCB., Results: Of the 813 patients in the study (260 women and 553 men; mean [SD] age, 41.2 [11.5] years), the mean MCCB composite score at baseline was 22.8 points below the normative mean, and the mean (SEM) total change in the MCCB during receipt of placebo was 1.8 (0.2) T-score points (95% CI, 1.40-2.18), equivalent to a change of 0.18 SD. Practice effects in the 7 studies in which there was a prebaseline assessment were essentially identical to the postbaseline placebo changes. Baseline factors associated with greater improvements in the MCCB during receipt of placebo included more depression/anxiety (F1,438 = 5.41; P = .02), more motivation (F1,272 = 4.63; P = .03), and less improvement from screening to baseline (F1,421 = 59.32; P < .001)., Conclusions and Relevance: Placebo effects were minimal and associated with the number of postbaseline assessments and several patient characteristics. Given that the patients performed 2.28 SDs below normative standards on average at baseline, a mean placebo-associated improvement of less than 0.2 SD provides evidence that ceiling effects do not occur in these trials. These minimal changes in the MCCB could not be responsible for effective active treatments failing to separate from placebo.

Objective: The authors sought to evaluate the efficacy and safety of ABT-126, a selective α7 nicotinic receptor partial agonist, in stable patients with schizophrenia., Method: A 12-week, double-blind, placebo-controlled, parallel-group phase 2 study was conducted in 22 centers in the United States. Clinically stable patients with schizophrenia were randomly assigned to receive once-daily dosing with 10 mg of ABT-126, 25 mg of ABT-126, or placebo. The primary efficacy measure was change from baseline to week 12 on the MATRICS Consensus Cognitive Battery (MCCB) composite score compared with placebo, tested by a one-sided t test. Secondary measures included MCCB domain scores and UCSD Performance-Based Skills Assessment total score, each tested by two-sided t tests., Results: A total of 207 subjects were randomized, of whom 165 (81%) completed the study. ABT-126 showed an improvement that fell short of significance on the MCCB composite score at week 12 (least squares mean difference from placebo, 1.3 and 1.5 for the 10 mg and 25 mg groups, respectively). A significant treatment-by-smoking status interaction was observed on the mean change from baseline to final MCCB composite score: nonsmokers (N=69) demonstrated a difference from placebo of 2.9 (SE=1.4) in the 10 mg group and 5.2 (SE=1.6) in the 25 mg group, whereas no differences were observed in smokers (N=113). Among the nonsmokers in the ABT-126 25 mg group (N=19), significant improvements compared with placebo occurred at final assessment for verbal learning (least squares mean difference=5.5, SE=1.9), working memory (least squares mean difference=5.4, SE=2.0), and attention/vigilance (least squares mean difference=8.7, SE=2.5). The most frequently reported adverse events for ABT-126 were dizziness, diarrhea, and fatigue (all <8% incidence)., Conclusions: ABT-126 demonstrated a procognitive effect in nonsmoking subjects, particularly in verbal learning, working memory, and attention.

If treatments for cognitive impairment are to be utilized successfully, clinicians must be able to determine whether they are effective and which patients should receive them. In order to develop consensus on these issues, the International Society for CNS Clinical Trials and Methodology (ISCTM) held a meeting of experts on March 20, 2014, in Washington, DC. Consensus was reached on several important issues. Cognitive impairment and functional disability were viewed as equally important treatment targets. The group supported the notion that sufficient data are not available to exclude patients from available treatments on the basis of age, severity of cognitive impairment, severity of positive symptoms, or the potential to benefit functionally from treatment. The group reached consensus that cognitive remediation is likely to provide substantial benefits in combination with procognitive medications, although a substantial minority believed that medications can be administered without nonpharmacological therapy. There was little consensus on the best methods for assessing cognitive change in clinical practice. Some participants supported the view that performance-based measures are essential for measurement of cognitive change; others pointed to their cost and time requirements as evidence of impracticality. Interview-based measures of cognitive and functional change were viewed as more practical, but lacking validity without informant involvement or frequent contact from clinicians. The lack of consensus on assessment methods was viewed as attributable to differences in experience and education among key stakeholders and significant gaps in available empirical data. Research on the reliability, validity, sensitivity, and practicality of competing methods will facilitate consensus., (© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Introduction: ABT-288 is a highly potent histamine-3 receptor antagonist that has demonstrated pro-cognitive effects in preclinical models relevant to schizophrenia. This study evaluated the efficacy and safety of two doses of ABT-288 in the treatment of cognitive impairment associated with schizophrenia., Methods: A randomized, double-blind, placebo-controlled, parallel-group 12-week study was conducted at 23 centers in the United States. Clinically stable subjects with schizophrenia were randomized in an equal ratio to ABT-288 10 mg, ABT-288 25 mg, or placebo once daily while continuing their antipsychotic regimen. The primary efficacy measure was the change from baseline to day 84 evaluation on the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) composite score vs placebo. Secondary measures included cognitive functioning and psychiatric scales. Safety assessments and sparse pharmacokinetic sampling were also conducted., Results: A total of 214 subjects were randomized. The mean baseline MCCB composite score was 28.4. Approximately 80% of subjects completed the study. The MCCB composite score mean change from baseline to day 84 was numerically worse for both the 10 mg (1.90, P = .618) and 25 mg (0.64, P = .946) doses of ABT-288 vs placebo (2.19). Results from the secondary measures were consistent with the primary analysis. Subjects' schizophrenia symptoms remained stable throughout the study as evidenced by stable Positive and Negative Syndrome Scale scores. Overall, study medication was tolerated; however, an increased incidence of psychosis-related and sleep-related adverse events was associated with ABT-288., Discussion: Neither dose of ABT-288 resulted in cognitive improvement in clinically stable adults with schizophrenia., (© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: ABT-288, a highly selective histamine-3 receptor antagonist, demonstrated efficacy across several preclinical cognitive domains, and safety in healthy subjects and elderly volunteers., Objective: Evaluate the efficacy and safety of ABT-288 in subjects with mild-to-moderate Alzheimer's dementia., Methods: The study used a randomized, double-blind, placebo- and active-controlled, parallel group design with pre-defined futility criteria to permit early study termination. A total of 242 subjects were randomized in an equal ratio to ABT-288 1 mg or 3 mg, donepezil 10 mg, or placebo once daily for 12 weeks. The primary efficacy endpoint was the change from baseline to final evaluation on the 13-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score., Results: The study was prematurely terminated because futility criteria were met. Point estimates on the ADAS-Cog scores for both ABT-288 dose groups were numerically inferior to placebo but no statistical differences were detected. Donepezil demonstrated statistically significant improvement. Adverse events were generally mild and self-limiting., Conclusion: ABT-288 did not demonstrate efficacy in the symptomatic treatment of Alzheimer's dementia.

Pregabalin has shown clinical efficacy for treatment of neuropathic pain syndromes, partial seizures, and anxiety disorders. Five studies in healthy volunteers are performed to investigate single- and multiple-dose pharmacokinetics of pregabalin. Pregabalin is rapidly absorbed following oral administration, with peak plasma concentrations occurring between 0.7 and 1.3 hours. Pregabalin oral bioavailability is approximately 90% and is independent of dose and frequency of administration. Food reduces the rate of pregabalin absorption, resulting in lower and delayed maximum plasma concentrations, yet the extent of drug absorption is unaffected, suggesting that pregabalin may be administered without regard to meals. Pregabalin elimination half-life is approximately 6 hours and steady state is achieved within 1 to 2 days of repeated administration. Corrected for oral bioavailability, pregabalin plasma clearance is essentially equivalent to renal clearance, indicating that pregabalin undergoes negligible nonrenal elimination. Pregabalin demonstrates desirable, predictable pharmacokinetic properties that suggest ease of use. Because pregabalin is eliminated renally, renal function affects its pharmacokinetics.

This was a multicenter, double-blind (DB), placebo-controlled, randomized discontinuation trial to evaluate the efficacy of pregabalin monotherapy for durability of effect on fibromyalgia (FM) pain. The trial included a 6-week open-label (OL) pregabalin-treatment period followed by 26-week DB treatment with placebo or pregabalin. Adults with FM and 40-mm score on 100-mm pain visual analog scale (VAS) were eligible. During OL weeks 1-3, patients received escalating dosages of pregabalin to determine their optimal dosages. During OL weeks 4-6, patients received their optimal fixed dosages (300, 450, 600mg/d). To be randomized, patients must have had 50% decrease in pain VAS and a self-rating of "much" or "very much" improved on Patient Global Impression of Change (PGIC) at the end of OL. Double-blind treatment was with placebo or the patient's optimal fixed dosage of pregabalin. Primary outcome was time to loss of therapeutic response (LTR), defined as <30% reduction in pain (from OL baseline) or worsening of FM. A total of 1051 patients entered OL; 287 were randomized to placebo, 279 to pregabalin. Time to LTR was longer for pregabalin versus placebo (P<.0001). Kaplan-Meier estimates of time-to-event showed half the placebo group had LTR by Day 19; half the pregabalin group still had not lost response by trial end. At the end of DB, 174 (61%) placebo patients met LTR criteria versus 90 (32%) pregabalin patients. Pregabalin was well tolerated, though 178 (17%) discontinued during OL for treatment-related adverse events (AE), and more pregabalin than placebo patients discontinued for AEs during DB. In those who respond, pregabalin demonstrated durability of effect for relieving FM pain.

Pagoclone is a novel cyclopyrrolone that acts as a partial GABA(A) receptor agonist. Preclinical studies suggest that pagoclone may have clinical utility as an anxiolytic agent, as well as a reduced incidence of side-effects. The present study was conducted to determine whether pagoclone would affect healthy individuals' performances on neuropsychological measures as a function of dose within the projected therapeutic range. Twelve healthy adult subjects were randomly assigned to dosage groups in a 3-way crossover study. Participants were administered neuropsychological measures six hours following dosing on Day 1 and Day 6 of administration of the drug. Dose effects were noted on measures of alertness, learning, and memory and movement time. Significant effects were also noted on measures of alertness, learning and memory, information processing and psychomotor speed. Overall, the results of this small, preliminary study do not support a finding of behavioral toxicity for these doses of pagoclone. Rather, a pattern was found of transient and mild negative effects on learning and memory scores at the highest dose administered, though these changes were small and no longer evident by the sixth day of use.

This study assessed the abuse potential of pagoclone, a partial agonist at the gamma-aminobutyric acid type A (GABAA) benzodiazepine receptor site, in healthy recreational drug users. Twenty-three young adults, who reported past recreational use of sedative drugs or alcohol, participated in 4 sessions during which capsules containing pagoclone (doses: 1.2 mg, the higher end of the proposed therapeutic dose range, and 4.8 mg, a 4-fold higher dose), diazepam (dose, 30 mg), or placebo were randomly administered under double-blind conditions. Subjective ratings of mood, drug effects, and psychomotor tests were completed at regular intervals after ingesting the capsules. On most of the standardized measures of abuse potential, pagoclone (dose, 4.8 mg) was rated as being similar to diazepam. Both drugs increased the ratings of good effects and drug liking. However, pagoclone also produced some adverse mood effects that might limit its potential to be used recreationally, and it produced fewer sedativelike effects on some measures. In general, the results with these doses indicate that the abuse potential of pagoclone is similar to that of diazepam, although its profile as a partial agonist suggests that differences between the drugs may emerge at higher doses.

Objective: To describe and then compare an investigational carbapenem antibiotic, meropenem, with the only currently available antibiotic in this class, imipenem/cilastatin., Data Identification: An English language search using MEDLINE (1988-1993); Abstracts of the 31st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 1991; and Abstracts of the 32nd ICAAC, 1992., Study Selection: All current scientific publications were reviewed for study design and quality. Emphasis was placed on susceptibility and pharmacokinetic analysis. Phase 3 clinical trials are now being completed and have only been published in abstract form. Hence, conclusions derived regarding efficacy were tempered., Results: Meropenem is active against a broad spectrum of gram-positive and -negative pathogens including beta-lactamase producers. Meropenem appears to be two- to fourfold less active than imipenem against gram-positive organisms. Meropenem is two- to fivefold more active against enterobacteriaceae. The two compounds appear to be equally active against Pseudomonas aeruginosa. Pharmacokinetic disposition is also similar for imipenem and meropenem. Meropenem may exhibit greater tissue penetration. Meropenem is not labile to renal hydrolysis and can be administered without a competitive antagonist of dihydropeptidase, such as cilastatin. In clinical trials, meropenem appears to be as safe and effective as imipenem/cilastatin or ceftazidime in the treatment of infections involving soft tissue, urinary tract, upper respiratory tract, abdominal processes, and febrile neutropenic episodes., Conclusions: Meropenem is comparable to imipenem in terms of in vitro susceptibility pattern and pharmacokinetic disposition. Overall, meropenem seems to offer promise as the second of the carbapenem class of antibiotics. Clinical data are preliminary, and further data are needed.

Digoxin was administered to an 18-day-old infant who showed evidence of cardiac failure. When a Doppler echogram revealed a patent ductus, indomethacin was administered for medical management. Therapeutic digoxin doses then resulted in toxic serum concentrations of 8.2 ng/ml. Serum creatinine rose accordingly. Although this patient did not manifest signs of digoxin toxicity, practitioners should be alerted to the potential complications of these commonly used agents.

The financial impact of pharmacist participation on a medical team in a tertiary-care teaching hospital was studied prospectively. Two medical teams, one with and one without a pharmacist, operated simultaneously for 11 months. Physicians and a pharmacist on the teams rotated monthly during the first five months of the study. Subsequently, the hospital administrator, who was unaware that the controlled study was under way, permanently assigned an attending physician to the team that did ot have a pharmacist. After patients' discharge, pharmacy costs, pharmacy charges, hospital charges, and length of stay (LOS) were compared for the two teams. Data analysis was separated into four phases: phase 1, during which attending physicians rotated monthly; phase 2, with a permanent attending physician; phase 3, which encompassed the entire 11 months; and phase 4, which encompassed the 11-month period but omitted patients whose LOS exceeded 30 days. Data were analyzed for a total of 619 patients on the two teams. In phase 1, the team with a pharmacist had significantly lower per-patient pharmacy costs, pharmacy charges, hospital charges, and LOS. In phase 2, no significant differences were found between the teams. In phase 3, the only significant difference was that the team with a pharmacist had lower pharmacy costs and pharmacy charges. In phase 4, the team that included a pharmacist had significantly lower pharmacy costs ($105 difference), pharmacy charges ($368 difference), hospital charges ($2065 difference), and LOS (1.3-day difference). Participation of pharmacists on the medical team can significantly reduce pharmacy costs and charges, hospital charges, and LOS.